Integrin is a family of receptors that have cell adhesion molecules as ligands, and mediate cell-to-cell and cell-to-extracellular matrix adhesions. Integrins directly participate in preservation of cell shape, anchorage for cell migration, and intra- and extracellular signal transduction. Therefore, integrins play important roles in a range of biological events including cell survival, movement, proliferation, development and differentiation.
Integrin is a heterodimeric transmembrane glycoprotein consisting of α and β chains. To date, various kinds of α and β chains have been known, and thus more than 20 integrins have been identified based on combination of the α and β chains (Trends Pharmacol., Sci., 21, 29 (2000)). In addition to the integrins, a number of cell adhesion molecules including, proteins that constitute extracellular matrix such as, collagen and vitronectin, proteins involved in immune and/or inflammatory cells adhesion such as, VCAM-1 and ICAM-1, and proteins involved in blood coagulation such as, fibrinogen and von Willebrand factor have been identified as integrin ligands (Cell, 69, 11 (1992)).
The αvβ3 integrin comprising αv- and β3-chains is also known as vitronectin receptor. Although vitronectin is the main ligand for αvβ3 integrin, some other proteins with RGD sequence such as fibronectin, fibrinogen and osteopontin are also known as αvβ3 integrin ligands.
It is known that αvβ3 integrin is expressed on a wide variety of adhesive cells. Among them, much attention has been given to the pathophysiological role of αvβ3 integrin expressed on cells where cell adhesion, migration, or proliferation is activated with the development of disease state. For example, after angioplasty, abnormal migration and proliferation of vascular smooth muscle cells often causes neointimal hyperplasia resulting in restenosis. Similarly, in cancer tissues, abnormal migration and proliferation of vascular endothelial cells accelerates angiogenesis. Moreover, it has been shown in animal models of progressive diseases that the expression of αvβ3 integrin is increased in defective cells, and that disease symptoms can be prevented by administration of antibodies or synthetic peptides which inhibit αvβ3 integrin (Curr. Pharm. Des., 3, 545 (1997)). Therefore, it is suggested that αvβ3 integrin may play an important role in the initiation and progression of restenosis and angiogenesis. Besides these two conditions, αvβ3 integrin has also been shown to be involved in other diseases including osteoporosis, rheumatoid arthritis, cancer metastasis, diabetic retinopathy, inflammatory diseases and viral infections (Curr. Biol., 3, 596 (1993); Cell. Mol. Life Sci., 56, 427 (1999); Drug Discovery Today, 5, 397 (2000)).
From the information above, it is assumed that inhibition of αvβ3 integrin might cure diseases that are accompanied with cells adhesion, migration or proliferation. Therefore, it is expected that αvβ3 integrin inhibitors may be useful as a novel type of antirestenotic agents, antiarterioscierotic agents, anticancer agents, antiosteoporosis agents, antiinflammatory agents, antiimmune agents, and agents for eye diseases.
Beside αvβ3 integrin, αIIbβ3 integrin or GPIIb/IIIa, another integrin closely related to αvβ3 integrin, has been shown to be highly involved in platelet aggregation. As inhibitors of αvβ3 integrin that also suppress αIIbβ3 integrin may cause breeding adverse effects, and may be inappropriate for repeated administration, αvβ3 integrin inhibitors with high selectivity for αvβ3 integrin as opposed to αIIbβ3 integrin have long been desired.
As far as the present inventors know, no therapeutic agent with highly selective αvβ3 integrin inhibitory activity has, so far, been developed. Therefore, under the present situation where diseases that involve αvβ3 integrin have been increasing with the aging population, it is necessary to develop inhibitors with high selectivity for αvβ3 integrin as opposed to αIIbβ3 integrin.
To date, quite a lot of compounds having αvβ3 integrin inhibitory activity have been reported (cf. U.S. Pat. No. 5,990,145, WO 98/18461, WO 99/38849, WO99/52872, etc.) For example, WO 99/38849 discloses (2S)-2-benzenesulfonylamino-3-[3-chloro-4-[4-(1,4,5,6-tetrahydropyrimidin-2-yl)piperazin-1-yl]benzoylamino]propanoic acid represented by the following formula (A-1, Example 59), and it reports that this compound has a potent αvβ3 integrin inhibitory activity (IC50 value: 3.5 nM) and GPIIb/IIIa inhibitory activity (IC50 value: 0.2 nM or less).

In addition, WO 99/52872 discloses (2S)-2-benzenesulfonylamino-3-[3-fluoro-4-[[4-(1,4,5,6-tetrahydropyrimidin-2-yl)amino]-piperidin-1-yl]benzoylamino]propanoic acid represented by the following formula (A-2, Example 52), and it reports that this compound has a potent αvβ3 integrin inhibitory activity (IC50 value: 1.0 nM or less) and GPIIb/IIIa inhibitory activity (IC50 value: 1.0 nM or less).

However, the chemical structures of these compounds are completely different from those of the compounds of the present invention as described below, and these compounds have a potent GPIIb/IIIa inhibitory activity, which is also different from the compounds of the present invention.
The present inventors have intensively studied, and have found that a novel aryl-substituted alicyclic compound of the formula (I) has a potent αvβ3 integrin inhibitory activity, and that it is useful as a preventive or therapeutic agent for diseases with which αvβ3 integrin is involved, and have accomplished the present invention.